There are approximately 50 different types of adenoviruses (Ad) which are associated with a significant number of human respiratory, gastrointestinal and ocular infections. Ad types 2/5 are also being used as vectors for gene delivery in clinical trials to treat a variety of acquired and inherited diseases. Despite a wealth of information on the virus structure and its life-cycle, there is a lack of knowledge of the receptors used by certain Ad types associated with severe ocular infections (epidemic keratoconjunctivitis, EKC). Specifically, Ad types belonging tO subgroup D (Ad37, Ad19a, Ad8) exhibit ocular cell tropism and cause EKC. Recent studies indicate that Ad37 recognizes a 50 kDa protein receptor that is preferentially expressed on conjunctival cells. This proposal seeks to identify the Ad37 receptor and confirm its role in ocular infection by other subgroup D adenoviruses. Further studies will also examine the role of integrins alpha-v-beta3 and alpha-v-beta3 and cell signaling pathways in Ad4nduced ocular infections. These molecules serve as coreceptors for Ad2 internalization; however, their role in infection of conjunctival, cornea and other ocular cell types by subgroup D viruses, has not been established. Finally, structural analyses of subgroup D Ads complexed with their primary receptor or with coreceptors or both molecules will be performed using cryoelectron microscopy or X-ray crystallography. These studies will allow a more complete understanding of the multistage process of adenovirus infection. They could also lead to the development of antiviral compounds to restrict ocular infection by subgroup D adenoviruses.